The present invention relates to a process for preparing optically active indoline-2-carboxylic acid by an optical resolution, which comprises subjecting a racemic ester of (R,S)-indoline-2-carboxylic acid having the general formula [(R,S)-I]: ##STR1## wherein R is an alkyl or alkenyl group having 1 to 10 carbon atoms; an alkyl or alkenyl group having 1 to 10 carbon atoms substituted with either hydroxyl group or a halogen atom, or simultaneously substituted with both hydroxyl group and a halogen atom; a substituted or unsubstituted aromatic hydrocarbon group; or substituted or unsubstituted phenyl or benzyl group, to the action of an enzyme or a microorganism having a stereo-selective esterase activity, which is capable of asymmetrically hydrolyzing the racemic ester [(R,S)-I] to give optically active indoline-2-carboxylic acid having the formula [II*]: ##STR2## so as to produce the hydrolysis product, i.e. optically active indoline-2-carboxylic acid [II*] and an unreacted optically active ester of indoline-2-carboxylic acid having the general formula [I*]: ##STR3## wherein R is as above, isolating each optically active form, and further, if necessary, hydrolyzing the obtained optically active ester [I*] to give an optical antipode of the acid [II*].
The present invention also relates to a process for preparing optically active indoline-2-carboxylic acid by immobilizing the microorganism or the enzyme on the support and utilizing the affinity difference between indoline-2-carboxylic acid and ester of indoline-2-carboxylic acid to the immobilizing support, which comprises eluting hydrophilic optically active indoline-2-carboxylic acid with water or a buffer solution, and then hydrolyzing with alkali optically active ester of indoline-2-carboxylic acid which is adsorbed and retained on the support, followed by elution of optically acitve indoline-2-carboxylic acid [II*] which has an opposite optical rotation based on the previously obtained optically active indoline-2-carboxylic acid.
The process of the present invention can produce (R)-indoline-2-carboxylic acid and ester of (S)-indoline-2-carboxylic acid, (S)-indoline-2-carboxylic acid and ester of (R)-indoline-2-carboxylic acid, or simultaneously both (R)- and (S)-indoline-2-carboxylic acids.
These optically active indoline-2-carboxylic acids can be used as a starting material for synthesizing various kinds of drug. For example, (S)-indoline-2-carboxylic acid can be used for synthesizing (S)-1-[(S)-mercapto-2-oxopropyl]-indoline-2-carboxylic acid having the formula: ##STR4## which is an antihypertensive drug effective as an inhibitor for Angiotensin I converting enzyme, and the like (J. Med. Chem. 26, 394 (1983)).
Hitherto, these optically active indoline-2-carboxylic acids have been prepared by using the agent for optical resolution as follows: ##STR5##
However, these processes are too complicated and thus more simple process for preparing optically active indoline-2-carboxylic acid or optically active ester of indoline-2-carboxylic acid has been desired for the production on a large scale.
The present inventors have studied, in order to establish a simple process for preparing optically active indoline-2-carboxylic acid, by esterifying indoline-2-carboxylic acid with various alcohols and then subjecting the obtained ester to the action of a microorganism or an enzyme. As the result, it was found by the present inventors as follows:
(1) Racemic ester of (R,S)-indoline-2-carboxylic acid was subjected to the action of an enzyme derived from the animal pancreas; the microorganism of the genus such as Aspergillus, Bacillus, Streptomyces, Arthrobacter, Saccharomyces, Aeromonas, Acidiphilium, Brevibacterium, Corynebacterium, Trichosporon or Pseudomonas; or an enzyme derived from any of these microorganisms to be asymmetrically hydrolyzed to give (R)-indoline-2-carboxylic acid and ester of (S)-indoline-2-carboxylic acid, which were then separated and extracted with an organic solvent to give (R)-indoline-2-carboxylic acid [(R)-II] and ester of (S)-indoline-2-carboxylic acid [(S)-I], further [(S)-I] being hydrolyzed with alkali or an enzyme to give (S)-indoline-2-carboxylic acid [(S)-II].
(2) Racemic ester of (R,S)-indoline-2-carboxylic acid was subjected to the action of the microorganism of the genus such as Alcaligenes, Nadsonia, Rhodotorula, Torulopsis, Protaminobacter, Pseudomonas, Arthrinium, Aspergillus, Cephalosporium, Echinopodospora, Emericellopsis, Hypocrea, Isaria, Lepista, Nectria, Phialophora, Pestalotiopsis, Podospora, Moniliella, Kluyveromyces, Schizosaccharomyces, Wickerhamia, Arthrobacter, Brevibacterium, Botryoascus, Candida, Citeromyces, Debaryomyces or Hormoascus, or an enzyme derived from any of these microorganisms to be asymmetrically hydrolyzed to give (S)-indoline-2-carboxylic acid [(S)-II] and ester of (R)-indoline-2-carboxylic acid [(R)-I], which were then separated and extracted with an organic solvent to give [(S)-II] and [(R)-I], further [(R)-I] being hydrolyzed with alkali or an enzyme to give [(R)-II].
(3) The above enzyme or microorganism was immobilized on a hydrophobic support so that, by utilizing an affinity difference between indoline-2-carboxylic acid and ester of indoline-2-carboxylic acid to the immobilizing support, hydrophilic indoline-2-carboxylic acid was eluted with water or a buffer solution and then ester of indoline-2-carboxylic acid, which was adsorbed and retained on the support, was hydrolyzed with alkali to elute optically active indoline-2-carboxylic acid [II*] which had an opposite optical rotation based on the previously obtained optically active indoline-2-carboxylic acid.
Hitherto, it has not yet been reported that optically active indoline-2-carboxylic acid can be prepared by the asymmetric hydrolysis of ester of indoline-2-carboxylic acid with enzyme or microorganism, that racemic ester of indoline-2-carboxylic acid is asymmetrically hydrolyzed with immobilized enzyme while the reaction product is simultaneously separated, and then unreacted ester adsorbed on the support is hydrolyzed with alkali, the product of hydrolysis being eluted, and that these processes can be carried out continuously.